Obesity and its co-morbidities cause about 400,000 deaths and cost more than $140 billion per year in USA. However, current treatment options for obesity are very limited. Vagal nerve stimulation (VNS) as a potential therapy for treating obesity has been explored in both laboratory and clinical settings. However, there is lack of systematic studies investigating the effects of various stimulation parameters and configurations on food intake and body weight. Consequently, no clinically relevant methodologies are currently available. In this project, we propose an innovative method of VNS for treating obesity by optimizing methodologies and providing automated delivery of electrical stimulation upon food ingestion. Our preliminary data in obese rats have demonstrated a significant and clinically relevant weight loss, attributed to the inhibition in food intake. The main aim of this project is o prove the feasibility of the proposed VNS for treating obesity in a large animal model of obesity using an implantable pulse generator. Specific objectives are as follows: 1) to derive most effective parameters for VNS to inhibit food intake in a swine model of obesity. Experiments are designed to obtain most effective stimulation frequencies, pulse width and stimulation configurations; 2) to study the efficacy and safety of chronic VNS using optimized stimulation parameters in treating obesity in pigs and also to explore possible mechanisms involving autonomic functions, gastric motility and gastrointestinal hormones, such as orexigenic hormone, ghrelin, and anorexigenic hormones, glucagon-like peptide-1 and polypeptide YY; The performance of on-demand meal-triggered VNS method in reducing body weight will be compared with the conventional VNS; 3) to develop an algorithm and use it to detect food intake and automatically initiate VNS upon meal ingestion. It will be designed based on changes in autonomic functions upon food intake. The autonomic functions will be assessed using spectral analysis of the heart rate variability signal that is obtained from stimulation electrodes. A comprehensive and competitive team has been assembled with expertise in neuromodulation, software and device development, obesity, and surgery. A consulting statistician is also included in the team. The accomplishment of this project will prove the feasibility of the proposed method for treating obesity.